Synthesis, molecular modelling and docking studies of new thieno[2,3-b:4,5-b′] dipyridine compounds as antimicrobial agents

A series of substituted thieno[2,3-b:4,5-b′]dipyridine compounds were synthesized based on the reactions of 2-acetyl-3-aminothieno[2,3-b]pyridine derivative 1 with 1,3-bifunctional reagents (malononitrile, cyanoacetamide, acetylacetone, ethyl acetoacetate) and/or DMF-DMA. The frontier molecular orbitals of the produced derivatives were obtained from DFT/B3LYP calculations to investigate their structural and energetic properties. The data revealed that they had a low energy gap (ΔE_H-L), 2.32–3.39 eV, where compounds 3 and 6 displayed the smallest and greatest values, respectively. Meanwhile, the antibacterial activity of synthesized thieno[2,3-b:4,5-b′]dipyridine analogues was tested against four bacterial strains. Derivatives 2, 3, 5 and 8 exhibited good activity against Gram-positive bacteria rather than Gram-negative comparable to the ampicillin drug reference. Also, thienodipyridine analogues 2, 3, 5 and 8 displayed good activity in general, but against Gram-positive rather than Gram-negative bacteria. Meanwhile, the SAR of the synthesized analogues was discussed to describe the effect of their substituents on both two Gram-positive bacteria (S. aureus and B. subtilis) and two Gram-negative bacteria (S. typhimurium and E. coli). Also, the molecular docking estimation was applied on these hybrids to inspect their binding interactions toward the E. coli DNA gyrase B active site (PDB code: 1AJ6).